On the pathogenesis of perforin defects and related immunodeficiencies

Abstract

Perforin is a prototype effector molecule of cytotoxicity-mediated immune cells. Following cell triggering, perforin inserts into the plasma membrane and undergoes polymerization to form pores that may lead to osmotic lysis of target cells and allow granzymes and other granule components to enter the target cells and to initiate apoptotic events. The perforin deficiency has recently been identified as an underlying cause of familial hemophagocytic lymphohistiocytosis (FHL) (Ref. 1xPerforin gene defects in familial hemophagocytic lymphohistiocytosis. Stepp, S.E. et al. Science. 1999; 286: 1957–1959Crossref | PubMed | Scopus (715)See all References1), a severe inherited human disorder characterized by a major immune dysregulation that invariably leads to death of patients unless treated with bone-marrow transplantation.In a recent Trends article2xPerforin: more than just an effector molecule. Stepp, S.E. et al. Immunol. Today. 2000; 21: 254–256Abstract | Full Text | Full Text PDF | PubMed | Scopus (96)See all References2, Stepp and colleagues offered a provocative hypothesis on the possible role of perforin not only as an effector molecule, but also as an immune regulator. There is, in fact, ample experimental evidence in the literature over the past six years to show that absence of perforin function shifts the antigen kinetics in various viral and intracellular bacteria infections but also has an influence on the half-life of antigen presenting cells that present new peptides via class I-MHC (Ref. 3xMolecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. Kagi, D. et al. Annu. Rev. Immunol. 1996; 14: 207–232Crossref | PubMed | Scopus (491)See all References3). Perforin also influences the destruction of solid peripheral tissue cells and the release of possible ‘ignored’ self-antigens; therefore perforin might influence autoimmune processes. We feel that the Trends article assigning a regulatory role to perforin might be misleading. Immune regulation is a common term that has been suffered from misuse too many times; in this context, perforin should not be added.In the case of FHL, perforin deficiency results in a severe immune dysregulation, but this effect should not necessarily be explained on the ground of a perforin-mediated regulatory effect. Indeed, the various pathological events that characterize both FHL and related immunodeficiencies, including Chediak–Higashi and Griscelli syndrome4.xPartial albinism with immunodeficiency (Griscelli syndrome). Klein, C. et al. J. Pediatr. 1994; 125: 886–895Abstract | Full Text | Full Text PDF | PubMed | Scopus (160)See all References, 5.xGriscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene. Pastural, E. et al. Nat. Genet. 1997; 16: 289–292Crossref | PubMed | Scopus (293)See all References, both characterized by the inability to release perforin-containing granules, can reflect the impaired effector function of perforin. The following explanation appears more likely: the whole clinical picture would stem from the inability of cytolytic effector cells to clear the infecting pathogen. Although T-cell-mediated recognition of pathogen-derived peptides leads to T-cell activation and clonal expansion, the resulting cells fail to kill the infected cells and thus to remove the source of antigen stimulation. On the other hand, this persistent, antigen-driven T-cell activation results in the production of large quantities of cytokines, including interferon γ (IFN-γ) and granulocyte–macrophage colony-stimulating factor (GM-CSF), two important macrophage activators. The sustained macrophage activation (and recruitment) results in tissue infiltration and in the production of high levels of tumour necrosis factor α (TNF-α), interleukin 1 (IL-1) and IL-6, which play a major role in the various clinical symptoms and tissue damage. Remarkably, the so-called ‘accelerated phases’ characteristic of Chediak–Higashi and Griscelli syndrome, display similar pathologic and clinical features. A different picture occurs in the X-linked lymphoproliferative disease (XLP) (Ref. 6xThe X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Sayos, J. et al. Nature. 1998; 395: 462–469Crossref | PubMed | Scopus (640)See all References6): in these patients, the inability to control Epstein–Barr virus (EBV) infections is consequent to a major dysfunction of 2B4 receptor, which exerts inhibitory instead of activating function7xX-linked lymphoproliferative disease: 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein–Barr virus-infected cells. Parolini, S. et al. J. Exp. Med. 2000; 192: 337–346Crossref | PubMed | Scopus (325)See all References7.In conclusion, the self destructive reactions occurring in FHL and related immunodeficiencies would involve the lack of perforin viewed as an effector molecule rather than as a molecule regulating the immune response.